Immune Modulating Antibody–Drug Conjugate (IM-ADC) for Cancer Immunotherapy

Antibody–drug conjugate (ADC)
and immune checkpoint blockade
(ICB) offer promising approaches for cancer treatment. Here, we describe
an ADC constructed by conjugating anti-PD-L1 THIOMAB with a bifunctional
immunomodulator D18 via a redox-cleavable linker. The
resulting ADC HE-S2 not only triggers a potent antitumor
immune response by blocking the PD-1/PD-L1 interaction and activating
the Toll-like receptor 7/8 (TLR7/8) signaling pathway but also upregulates
its targeted PD-L1 expression via epigenetic regulation and/or IFN-γ
induction, thus conferring more sensitivity to the PD-1/PD-L1 blockade.
We identify that ADC HE-S2 treatment could lead to more
pronounced tumor suppression than the treatment of D18 in combination with the anti-PD-L1 antibody. Accordingly, this study
provides a novel ADC strategy to enhance the antitumor immune response
to ICB therapy.